Is most complex trait variation caused by a few common alleles, or is it largely due to the aggregate contributions of many rare variants? How large are per-locus allelic effects on quantitative traits? Is effect size correlated with allele frequency across loci? These are questions of import throughout biology. Mutation- selection balance predicts that polymorphic loci will have rare alleles while balancing selection models predict intermediate allele frequencies. The respective contributions of these evolutionary mechanisms determines the relevance of standing variation to adaptive evolution and the extent to which quantitative trait evolution is limited by mutation as opposed to selection. In human health, the so-called common disease/common variant hypothesis is a statement on these conditions and its validity has clear clinical implications. The proposed studies advance ongoing experiments using the model plant Mimulus guttatus to provide a rigorous exploration of the genetic and ecological factors that maintain genetic variation in natural populations. The aims are to determine sequence-level determinants of variation in fitness-related traits. This research involves a combination of classical and modern genetics, molecular biology, statistical modeling, and field experimentation. The research should determine not only whether natural selection maintains genetic variation in ecologically important traits, but will begin to elucidate the particular selective agents that are involved. The third aim also develops a novel procedure for population mapping of quantitative trait loci that is potentially applicable to a broad range of organisms. The proposed studies will train undergraduates, doctoral students, and postdoctoral researchers in each of the four years of the project. PUBLIC HEALTH RELEVANCE: The proposed studies directly investigate the genetic architecture of complex traits. Most chronic human diseases are complex traits and the dissection of genetic causes is a major research focus of the National Institutes of Health. Our experiments on the model plant Mimulus guttatus provide relevant results and 'proof-of-concept' of genetic methods for future health-related research.